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Genomic and functional characterization of the tumor-killing capacity of Imiquimod-activated plasmacytoid dendritic cells

ABSTRACT: Plasmacytoid dendritic cells (pDCs) are a subset of DCs that act as important modulators of anti-tumor immune responses. pDCs have been associated with poor prognosis of tumor patients. Despite this, upon TLR7 activation, pDCs have also been shown to acquire tumor killing capacities, and we previously provided evidence on the role of activated pDCs in eliminating tumor cells in vivo, independently of adaptive immunity. In this study we investigated the mechanism by which pDCs acquire tumor-killing capacities following TLR7/8 triggering by Imiquimod (IMQ). By combining pathway perturbation and analysis of transcriptome, surfaceome, secretome, and killing function, we identified the MAPKs and NF-kB pathways as important downstream mediators of the tumor-killing ability of these cells. JNK inhibition reduces killing by secreted factors whereas p38 or NF-kB inhibition enhances cell mediated killing. Analysis of surface and secreted proteins revealed differential control of expression and secretion by IFN-I/-II, MAPK and NF-kB, while indicating that a complex signaling network is necessary to shape the cytotoxic phenotype of activated pDCs. Our integrated analysis converged on a new pDCs killing gene signature that is predictive of survival in cohorts of melanoma patients. These newly identified markers will be instructive for the rationale design and interpretation of further single-cell and functional approaches aimed at studying the role of pDCs in the tumor microenvironment. These might pinpoint novel strategies to improve cancer management and treatment, by modulating the pDCs pro- vs anti-tumorigenic functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE255537 | GEO | 2025/05/28

REPOSITORIES: GEO

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